Transdermal nitroglycerin therapy may not prevent early postmenopausal bone loss

Abstract

Context: Osteoporosis is common among postmenopausal women; animal studies and human pilot studies support the concept of nitric oxide (NO) donors reducing bone mineral density loss.

Objective: The objective of the study was to evaluate whether NO donor, nitroglycerin, prevents postmenopausal bone loss.

Design: This was a 3-yr randomized, double blinded, single-center, placebo-controlled clinical trial.

Setting: The single-center study was conducted at the University of Medicine and Dentistry-Robert Wood Johnson Medical School (New Brunswick, NJ).

Participants: Participants included 186 postmenopausal women aged 40-65 yr, with lumbar bone mineral density (BMD) T-scores of 0 to -2.5.

Intervention: Women, stratified by lumbar T-score (<-1.50 and >or=-1.50) and years since menopause (<or=5 and >5 yr), were randomized to receive nitroglycerin ointment (22.5 mg as Nitro-Bid) or placebo ointment received daily for 3 yr. Both groups took 630 mg daily calcium plus 400 IU vitamin D supplements.

Measurements: BMD was measured at 6 months and annually by dual-energy x-ray absorptiometry. Percent change in lumbar vertebrae BMD was the primary outcome. Hip BMD, total body bone mineral content, and height were secondary outcomes.

Results: After 36 months of therapy, changes of -2.1% in the active group (n = 88) and -2.5% in the placebo group (n = 82) in lumbar spine BMD were seen (P = 0.59; 95% confidence interval -1.001, 1.975). Secondary outcomes also did not differ by intervention arm. The active group reported more headaches compared with the placebo group (57 vs. 14%, P < 0.001). Other adverse and serious adverse events were not different.

Conclusions: BMD changes did not substantially differ between postmenopausal women who received the dose of nitroglycerin tested, in comparison with a placebo. Once-daily dosing with 22.5 mg of transdermal-administered nitroglycerin was not effective (compliance adjusted dose was only approximately 16 mg/d); a sub-therapeutic dose.

Figures

Figure 1

NOVEL study participant recruitment and treatment scheme: standard dose of 2% Nitro-Bid (1.5 in., 22.5 mg) and reduced dose (0.5 in., 7.5 mg). The numbers of subjects in each treatment arm who were lost to follow-up at each clinic visit and the final number of subjects who completed the study are given.

Figure 2

Mean percent change from baseline to the given follow-up visit in BMD of the spine (A), total hips (B), femoral neck (C), and total body calcium (BMC) (D) by intention-to-treat analysis. Nitroglycerine-treated group, solid line, closed circles (active treatment group); calcium plus vitamin D group, dashed line, open circles (control group). There is no statistical difference between the two groups. Error bars, sem. The number of subjects in the active and placebo arms, respectively, are as follows: at 6 months, 92 and 90; at 12 months, 90 and 90; at 24 months, 88 and 86; at 36 months, 88 and 82.

Figure 3

Based on animal studies, the predicted representation of BMD responses to varying doses of nitrates and nitroglycerin use in the current clinical practice. This demonstrates the narrow therapeutic window of opportunity for the use of NO donors in improving human skeletal health (i.e. enhance BMD and decrease fractures) (24,38).